The Jackson Laboratory (Jackson) is a world-class research center focusing on the use of mammalian genetics to interrogate human disease. It is increasingly clear that most, if not all, diseases are ultimately influenced by a complex mix of genetic factors and gene-by-environment interactions. This highlights the need for research in tractable animal models to efficiently identify causal genetic variants and the molecular functions of their products using populations and detailed phenotyping that are not available in human studies. Jackson researchers currently lack the High Throughput Sequencing (HTS) required to fully tap the potential for rapid gene discovery and genome scale analyses offered by Jackson's vast collection of genetically diverse mice. With that capacity, investigators here will further their own research and enhance the value of our genetic and information resources to the international biomedical research community. HTS will provide rapid and cost-effective genome-scale sequencing and quantitative expression applications. It will increase the accuracy and depth of our genotyping, phenotyping and population identification experiments, enhancing discovery research leading to breakthroughs in human disease. Jackson scientists will use the Illumina GA-IIX system to: 1) define genetic variation in complex traits and a range of human diseases including epilepsy, diabetes and infertility, among others;2) examine gene expression and regulatory mechanisms implicated in human disease through RNA-Seq, ChIP-Seq, RIP-Seq and miRNA experiments, and 3) discover and characterize novel mutants 10 times more quickly than with current technologies. Funding is requested for a state-of-the-art Illumina GA-IIX HTS system, including the necessary bioinformatics support. The system includes: 1) an Illumina Genome Analyzer-IIX (GA-IIX) with Cluster Station and UPS, 2) a Laboratory Information Management System (LIMS) Server and GenoLogics software, 3) NetApp Servers for dedicated primary and backup storage of HTS data, and 4) Dedicated high-performance compute capacity for HTS analyses, 5) a Paired-End accessory to sequence through complex chromosomal rearrangements, and 6) upgraded GenomeStudio software to enable researchers to visualize and manipulate HTS data. Jackson has developed targeted re-sequencing and analysis protocols for the mouse genome;we have the expertise to utilize HTS and translate the massive and complex datasets into meaningful information. The HTS system will address unmet research needs of 14 Jackson researchers with 22 NIH funded grants ($13,871,118 current year;$8,398,793 direct cost). It will allow more than 6 additional researchers to explore innovative research avenues and support regional investigators. HTS data will be disseminated through NCBI's short read archive and Jackson databases (Mouse Genome Informatics;Mouse Phenome Database). Novel models, with enhanced characterization enabled by HTS, will be made available to the global research community through Jackson's existing mouse distribution programs.